Huntington's disease (HD) is an adult-onset autosomal dominant neurodegenerative disorder characterized clinically by cognitive, psychiatric and motor deficits which progress to severe disability and death. To date there are no affective treatments for HD. The mutated huntingtin (mhtt) protein is widely expressed in neuronal and non-neuronal cells, yet neurodegeneration is highly selective. Understanding the toxicity produced by mhtt and the basis for this selective neurodegeneration are likely to be critical in the design of effective therapies for the disease. The goal of this proposal is to understand the contribution of mhtt expressing astrocytes to neurodegeneration in HD. Astrocytes are critical to the proper function and development of the nervous system and have a newly appreciated role in controlling synaptic activity. Data from cell culture studies show that astrocytes may contribute to HD pathogenesis. However, no in vivo studies have been performed to systematically address this question. Therefore, I will study the contribution of astrocytes to disease pathogenesis in vivo by using conditional mhtt expressing mouse genetic models. Using these models and astrocytes obtained from them I will test three hypotheses: 1) The presence of the mhtt in astrocytes is (1) necessary and sufficient for the development of an HD phenotype; 2) the presence of mhtt in astrocytes causes impaired calcium homeostasis and glutamate release from astrocytes; and 3) The presence of mhtt in astrocytes leads to abnormalities in synaptic neurotransmission. Together these studies will help to define the role of mhtt within astrocytes in HD pathogenesis, and may lead to novel therapeutic approaches for treatment of HD. The research plan in this application is designed to allow the applicant to gain additional technical skills and tools for use in studying Huntington's disease pathogenesis, including cell biology and electrophysiology. These new capabilities, together with previous training in generating mouse genetic models of neurodegeneration, will make her a multidisciplinary scientist with the well-rounded set of skills necessary for attaining her long-term career goal of acquiring a tenure track faculty appointment at a major research institution. In addition to the technical skills obtained during this training period, the applicant will further her understanding of neurodegenerative diseases by attending seminars and journal clubs at UAB and outside scientific meetings. She will also take advantage of faculty development seminars and programs that help to teach the required skills and provide the knowledge necessary for a successful career as an independent research scientist including scientific and grant writing skills. Together, the career development component and research plan of this application will provide the candidate with a firm foundation on which to develop an independent laboratory focused on studying neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Project Narrative Huntington's disease (HD) is a devastating progressive adult-onset neurodegenerative disease. Currently, there is no treatment or a cure for HD. HD is one of the most common familial neurodegenerative disorders, with 30,000 clinically diagnosed HD patients and another 150,000 at risk for HD in the US.